Process for preparing crystalline from I of cabergoline

ABSTRACT

A process for producing crystalline form I of cabergoline, which process comprises crystallization of the desired form from a toluene/diethyl ether mixture comprising raw cabergoline, followed by recovery and drying of the resulting crystals. A new solvate form V of cabergoline, useful as an intermediate, is also provided.

[0001] The present invention concerns a new process for preparingcrystalline Form I of cabergoline.

[0002] Cabergoline is an ergoline derivative interacting with D2dopamine receptors and is endowed with different useful pharmaceuticalactivities and it is used in the treatment of hyperprolactinemia,central nervous system disorders (CNS) and other related diseases.

[0003] Cabergoline is the generic name of1((6-allylergolin-8beta-yl)-carbonyl)-1-(3-dimethylaminopropyl)-3-ethylurea,described and claimed in U.S. Pat No. 4,526,892. The synthesis ofcabergoline molecule is reported also in Eur. J. Med. Chem., 24,421,(1989) and in GB-2,103,603-B. Crystalline cabergoline Form I, ananhydrous not solvated form of cabergoline, was prepared bycrystallization from diethyl ether, as described in Il Farmaco, 50 (3),175-178 (1995).

[0004] Cabergoline Form I, like cabergoline, displays a significantinhibitory effect with regard prolactine and has therapeutic propertiesthat make it possible to treat patients who have pathological conditionsassociated with an abnormal prolactin level, thus is useful in humanand/or veterinary medicine. Cabergoline is also active, alone or incombination, in the treatment of reversible obstructive airwaysdiseases, for controlling intraocular pressure and for the treament ofglaucoma. It is also employed in the veterinary field, as antiprolactinagent and in cutting down drastically the proliferation of vertebrateanimals. The several uses of cabergoline are for example described inWO9948484, WO9936095, U.S. Pat No. 5705510, WO9505176, EP040,325.

[0005] Cabergoline Form I is particularly useful in the treatment ofParkinson's disease (PD), Restless Legs Syndrome (RLS), treatment ofdiseases like Progressive Supranuclear Palsy (PSP) and Multysystemicatrophy (MSA).

[0006] During our development work we discovered a new process forpreparing crystalline Form I.

[0007] Thus, the present invention concerns a new process for preparingForm I of cabergoline and a new solvate Form V of cabergoline useful asintermediate.

DESCRIPTION OF THE FIGURES

[0008]FIG. 1. XRD powder pattern of cabergoline Form I.

[0009]FIG. 2. DSC curve of cabergoline Form I.

[0010]FIG. 3. IR spectrum of cabergoline Form I (sample prepared by KBrpowder technique).

[0011]FIG. 4. Solid state ¹³C-NMR spectrum of cabergoline form I.

[0012]FIG. 5. XRD powder pattern of cabergoline solvate Form V.

[0013]FIG. 6. DSC curve of cabergoline solvate Form V.

[0014]FIG. 7. IR spectrum of cabergoline solvate Form V (sample preparedby KBr powder technique).

[0015]FIG. 8. Solid state ¹³C-NMR spectrum of cabergoline solvate FormV.

[0016] Form I can be readily prepared according to the present inventionstarting from crude material by crystallization from a toluene/diethylether mixture, through a new solvate form V of cabergoline. The presentprocess for preparing Form I shows advantages with respect to the oldone because of its greater reproducibility.

[0017] Characterisation

[0018] X-ray powder diffraction (XRD), differential scanning calorimetry(DSC), infrared (IR) spectroscopy and solid state ¹³C-NMR were used tocharacterise the new form.

[0019] X-Ray Powder Diffraction

[0020] Powder X-ray diffraction was performed using either a Scintag X1or X2 Advanced Diffraction System operating under Scintag DMS/NT© Ver1.30a and 1.36b respectively, and Microsoft Windows NT 4.0™ software.The system used a copper X-ray source maintained at 45 kV and 40 mA toprovide CuKα emission of 1.5406 Angstroms and a solid state peltiercooled detector. Beam aperture was controlled using tube divergence andanti-scatter slits of 2 and 4 mm and detector anti-scatter and receivingslits of 0.5 and 0.3 mm width. Data were collected from 2° to 30°two-theta using a step scan of 0.03°/point with a one second/pointcounting time. The samples were hand ground using a pestle and mortarand packed into an aluminum sample tray with a 12 mm (diam.)×0.5 mmcavity.

[0021] DSC

[0022] Measurements of differential scanning calorimetry were obtainedon a Mettler TA 4000 thermal analysis system. Approximately 8.5 mgsamples were accurately weighed into a DSC pan. The pans werehermetically sealed and a pinhole was punched into the pan lid. The useof the pinhole allows for pressure release, but still assures that thethermal reactions proceed under controlled conditions. The samples wereintroduced into the DSC oven and then heated at a rate of 5° C./min, upto a final temperature of 135° C.

[0023] IR Spectroscopy

[0024] IR spectra of cabergoline form I and V were obtained on a PerkinElmer FT-IR spectrophotometer PARAGON 1000. The sample were prepared byKBr powder technique registering the spectra on reflectance.

[0025] Solid state ¹³C-NMR

[0026] Solid state ¹³C-NMR spectra were obtained on a MSL 300 Brukerinstrument equipped with solid state facilities and variable temperaturemagic angle spinning probe. Cross polarisation experiments wereperformed by a decoupling field of 50 KHz and single pulse magic anglespinning experiments with recycle times ranging from 10 to 100 records.The x-ray powder diffraction pattern for Form I (FIG. 1) shows acrystalline structure with useful distinctive peaks at approximately9.7, 10.4 and 24.8 deg 2-theta. The DSC curve of Form I (FIG. 2)exhibits a melting endotherm at approximately 100°-105° C. Theintegrated melting endotherm has a heat of fusion of approximately 60J/g.

[0027] The IR spectrum of Form I is shown in FIG. 3.

[0028] The solid state ¹³C-NMR spectrum of form I is shown in FIG. 4.

[0029] These data indicate that cabergoline Form I is a crystallinepolymorph easily distinguishable by XRD and solid state ¹³C-NMRtechniques. DSC and IR are other two useful techniques to characterizethe polymorph. The process of the present invention for producingcrystalline cabergoline Form I is characterized by crystallisation froma toluene/diethyl ether mixture. The process comprises dissolving theraw final cabergoline, obtained as an oil through the synthesisdescribed in Eur. J. Med. Chem., 24, 421, (1989), in a suitable amountof a toluene/diethyl ether mixture, preferably about 1:1 mixture. Theresultant solution is then cooled at a temperature of from −25° to −9°C., preferably at about −12° C. for 17 hours. In these conditions, atoluene solvate is obtained, named Form V, that may be recovered bycommon procedures, for example by filtration under reduced pressure orby centrifugal filtration, followed by smoothly drying of the resultantsolid. The resultant crystals of Form V are then converted into form Iupon further drying. The crystals of Form I of cabergoline preparedaccording to the process of the present invention have preferably apolymorph purity >95%, more preferably >98%. Toluene solvate form V isalso object of the present invention. The x-ray powder diffractionpattern for Form V (FIG. 5) shows a crystalline structure.

[0030] The DSC curve of solvate Form V (FIG. 6) exhibits a meltingendotherm at approximately 60° -65° C.

[0031] The IR spectrum of solvate Form V is shown in FIG. 7. The solidstate ¹³C-NMR spectrum of form V is shown in FIG. 8.

[0032] These data indicate that cabergoline solvate Form V is easilydistinguishable by XRD, DSC and solid state ¹³C-NMR techniques. IR,combined with another analytical technique, is another method toidentify the solvate.

[0033] The solvate V of this invention is a true solvate having a fixedcomposition of about 0.5 toluene moles per mole of cabergoline.

EXAMPLE 1.

[0034] The oil obtained by purification on a chromatographic columnafter the final step of the synthetic path according to the preparationdescribed in Eur. J. Med. Chem., 24, 421, (1989) and containing 100 g ofpure cabergoline was dissolved in toluene to give 243 g of a cabergolinetoluene solution. The solution was introduced into a reactor pre-cooledat −12° C., and 182 g of toluene were added to give a 23.5%. w/wcabergoline concentration in this solvent. After cooling again at −12°C., 362 ml of diethyl ether were added. The mixture was cooled again at−12° C. and stirred at this temperature for about 17 hours. The obtainedprecipitate was filtered under vacuum and smoothly dried. The resultantcrystal solvate form V was identified by XRD, DSC, IR and NMR, datashown in FIGS. 5-8 respectively.

[0035] Yield was about 45% (w/w) on the basis of pure cabergolineinitial content.

EXAMPLE 2.

[0036] The crystal solvate form V obtained in example 1 was dried at atemperature of from 40° C. under vacuum to 65° C. under vacuum. Afterdrying, the resultant crystal form I was identified by XRD, DSC, IR andNMR, data shown in FIGS. 1-4 respectively. Yield was about 40% on thebasis of pure cabergoline initial content. The assayed polymorph puritywas >98%.

1. A process for producing cabergoline Form I, which process comprisescrystallisation of the desired crystalline form from a toluene/diethylether mixture comprising raw cabergoline, followed by recovery anddrying of the resulting crystals.
 2. A process according to claim 1 inwhich the crystallisation comprises dissolving raw cabergoline in atoluene/diethyl ether mixture, cooling the resulting solution,collecting the resulting solvate form V of cabergoline having the XRDpowder pattern of FIG. 5 and converting the solvate into cabergolineForm I by drying.
 3. A process according to claim 1 or 2 in which thetoluene/diethyl ether mixture is a 1:1 mixture.
 4. A process accordingto claim 2 or 3 in which the toluene/diethyl ether mixture is cooled toa temperature of from −25° to −9° C.
 5. A process according to claim 4,in which the toluene/diethyl ether mixture is cooled to a temperature ofabout −12° C.
 6. Solvate form V of cabergoline having the XRD powderpattern of FIG.
 5. 7. A process for producing solvate form V ofcabergoline as defined in claim 6, which process comprises dissolvingraw cabergoline in a toluene/diethyl ether mixture, cooling theresulting solution and collecting the resulting solvate form V ofcabergoline.
 8. A process according to claim 9 in which the toluene/diethyl ether mixture is a 1:1 mixture.
 9. A process according to claim7 or 8, in which the toluene/diethyl ether mixture is cooled to atemperature of from −25° to −12° C., and the solvate form V is collectedby filtration under reduced pressure or by centrifugal filtration,followed by smoothly drying the resulting solid.